Mice with the kd/kd genotype have an apparently normal state of health for the first eight weeks of life, but then develop a spontaneously occurring kidney disease which begins with leukocyte infiltrations and eventually leads to end stage renal disease. The genetic basis for this disease is a defect in an enzyme, designated Pdss2, that is needed for the isoprenylation of coenzyme Q (CoQ). Significant protection from renal disease occurs when the mice are given supplemental CoQ in the drinking water. As CoQ is essential for electron transfer in the mitochondrial respiratory chain and also serves as a lipid-soluble antioxidant, a defect in either or both of these functions could be the basis for the disease. When mutant mice were given Probucol, which is a lipid-soluble antioxidant, significant protection against disease also occurred, which suggests that oxidative stress is the critical determinant of disease. Conditional knockouts that do not express Pdss2 in the glomerular podocytes recapitulate the kidney disease phenotype of kd/kd mice. As the podocyte is not known to have an especially high energetic requirement, this also supports the hypothesis that the phenotype may result from podocyte damage caused by oxidative stress rather than a deficiency in the respiratory chain. This disease is similar in certain respects to focal segmental glomerulosclerosis (FSGS), and there is evidence that some patients with FSGS have mutant alleles of the same gene that is defective in kd/kd mice. These hypotheses will be addressed through the following specific aims: (1) To investigate the mechanisms by which therapy of Pdss2-related CoQ deficiency ameliorates renal disease, (2) To determine whether the kidney disease phenotype is affected by an absence of cyclophilin D, or by Pdss2 deficiencies in the collecting duct or ascending loop of Henle, and (3) To investigate the effects of variant alleles of PDSS2 in human patients with FSGS. PUBLIC HEALTH RELEVANCE: The kd/kd mouse has a lethal disease similar to FSGS caused by an inherited mitochondrial defect, but this disease can be prevented by treatment with CoQ or Probucol. There are very few, if any, other animal models of an inherited mitochondrial disease that can be successfully treated. This is therefore an important model, with the potential for helping to develop therapies for humans with similar disorders.